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Patient-derived xenograft (PDX) models are an effective preclinical in vivo platform for testing the efficacy of novel drugs and drug combinations for cancer therapeutics. Here we describe a repository of 79 genomically and clinically annotated lung cancer PDXs available from The Jackson Laboratory that have been extensively characterized for histopathologic features, mutational profiles, gene expression, and copy-number aberrations. Most of the PDXs are models of non–small cell lung cancer (NSCLC), including 37 lung adenocarcinoma (LUAD) and 33 lung squamous cell carcinoma (LUSC) models. Other lung cancer models in the repository include four small cell carcinomas, two large cell neuroendocrine carcinomas, two adenosquamous carcinomas, and one pleomorphic carcinoma. Models with both de novo and acquired resistance to targeted therapies with tyrosine kinase inhibitors are available in the collection. The genomic profiles of the LUAD and LUSC PDX models are consistent with those observed in patient tumors from The Cancer Genome Atlas and previously characterized gene expression-based molecular subtypes. Clinically relevant mutations identified in the original patient tumors were confirmed in engrafted PDX tumors. Treatment studies performed in a subset of the models recapitulated the responses expected on the basis of the observed genomic profiles. These models therefore serve as a valuable preclinical platform for translational cancer research. Significance: Patient-derived xenografts of lung cancer retain key features observed in the originating patient tumors and show expected responses to treatment with standard-of-care agents, providing experimentally tractable and reproducible models for preclinical investigations.

Our objective was to assess the incidence of drug bioaccumulation in critically ill COVID-19 patients with AKI receiving intermediate dose nadroparin for thrombosis prophylaxis. We conducted a Prospective cohort study of critically ill COVID-19 patients. In patients on intermediate dose nadroparin (5700 IU once daily) we assessed the incidence of bioaccumulation (trough anti-Xa level > 0.2 IU/mL) stratified according to presence of AKI. We quantified this association using multilevel analyses. To assess robustness of our observations, we explored the association between AKI and anti-Xa activity in patients receiving high dose nadroparin (> 5700 IU). 108 patients received intermediate dose nadroparin, of whom 24 had AKI during 36 anti-Xa measurements. One patient with AKI (4.2% [95%CI 0.1–21%]) and 1 without (1.2% [95%CI 0.03–6.5%]) developed bioaccumulation (p = 0.39). Development of AKI was associated with a mean increase of 0.04 (95%CI 0.02–0.05) IU/ml anti-Xa activity. There was no statistically significant association between anti-Xa activity and AKI in 51 patients on high dose nadroparin. There were four major bleeding events, all in patients on high dose nadroparin. In conclusion, Bioaccumulation of an intermediate dose nadroparin did not occur to a significant extent in critically ill patients with COVID-19 complicated by AKI. Dose adjustment in AKI may be unnecessary.

NADK2 encodes the mitochondrial form of nicotinamide adenine dinucleotide (NAD) kinase, which phosphorylates NAD. Rare recessive mutations in human NADK2 are associated with a syndromic neurological mitochondrial disease that includes metabolic changes, such as hyperlysinemia and 2,4 dienoyl CoA reductase (DECR) deficiency. However, the full pathophysiology resulting from NADK2 deficiency is not known. Here, we describe two chemically induced mouse mutations in Nadk2—S326L and S330P—which cause severe neuromuscular disease and shorten lifespan. The S330P allele was characterized in detail and shown to have marked denervation of neuromuscular junctions by 5 weeks of age and muscle atrophy by 11 weeks of age. Cerebellar Purkinje cells also showed progressive degeneration in this model. Transcriptome profiling on brain and muscle was performed at early and late disease stages. In addition, metabolomic profiling was performed on the brain, muscle, liver and spinal cord at the same ages and on plasma at 5 weeks. Combined transcriptomic and metabolomic analyses identified hyperlysinemia, DECR deficiency and generalized metabolic dysfunction in Nadk2 mutant mice, indicating relevance to the human disease. We compared findings from the Nadk model to equivalent RNA sequencing and metabolomic datasets from a mouse model of infantile neuroaxonal dystrophy, caused by recessive mutations in Pla2g6. This enabled us to identify disrupted biological processes that are common between these mouse models of neurological disease, as well as those processes that are gene-specific. These findings improve our understanding of the pathophysiology of neuromuscular diseases and describe mouse models that will be useful for future preclinical studies.

ObjectiveSentinel lymph node mapping has emerged as an alternative to lymphadenectomy in evaluating the lymph node status in endometrial cancer. Several pathological methods to examine the sentinel lymph node are applied internationally. The aim of this study was to determine the value of ultrastaging and to assess the ultrastaging method with the highest detection rate of metastases.MethodsA systematic review was conducted. Inclusion criteria were: pathologically-confirmed endometrial cancer with sentinel lymph node mapping, report of the histological outcomes, metastases found by hematoxylin and eosin staining and metastases found by ultrastaging were separately mentioned, and description of the ultrastaging method. The primary outcome was the detection of metastases found by ultrastaging that were not detected by routine hematoxylin and eosin staining. The secondary outcome was the difference in detection rate of metastases between several ultrastaging methods. Random effects meta-analyses were conducted.ResultsFifteen studies were selected, including 2259 patients. Sentinel lymph nodes were examined by routine hematoxylin and eosin staining. Subsequently, multiple ultrastaging methods were used, with differences in macroscopic slicing (bread-loaf/longitudinal), number of microscopic slides, and distance between slides, but all used immunohistochemistry. A positive sentinel lymph node was found in 14% of patients. In 37% of these, this was detected only by ultrastaging. Using more ultrastaging slides did not result in a higher detection rate. Bread-loaf slicing led to a higher detection rate compared with longitudinal slicing (mean detection rates 53% and 33%, respectively).ConclusionPathological ultrastaging after routine hematoxylin and eosin staining in endometrial cancer patients has led to an increased detection rate of sentinel lymph node metastases. Different ultrastaging methods are used, with a preference for bread-loaf slicing. However, due to the large heterogeneity of the studies, assessing which ultrastaging method has the highest detection rate of sentinel lymph node metastases was not possible.

Purpose To determine the added value of mammography in women with focal breast complaints and the utility of initial targeted ultrasound in this setting. Methods Women with symptomatic breast disease who were evaluated by breast imaging (mammography/digital breast tomosynthesis and ultrasound) between January 2016 and December 2016 in the Radboud University Medical Centre were included. We retrospectively collected the following data: date of birth, indication of imaging, visibility on mammography/ultrasound, whether biopsy was taken, additional findings, BI-RADS-classification, pathology and follow-up results. Results A total of 494 women were included (mean age 46.5, range 30 to 93). In 49 women (9.9%), symptomatic breast cancer was diagnosed, all visible during targeted ultrasound. The negative predictive value of targeted ultrasound was very high (99.8%). Additional findings on mammography were significantly more often malignant when the symptomatic lesion was also malignant (3.8% vs 70%, P Conclusions The contribution of mammography for cancer detection in women with focal breast complaints is very low when targeted ultrasound is performed. Additional findings are most common in patients with symptomatic breast cancer. Our results suggest that initial targeted ultrasound is a more appropriate initial tool for the evaluation of focal breast complaints. Mammography could be performed on indication only.

The Mouse Genome Database (MGD; http://www.informatics.jax.org) is the community model organism knowledgebase for the laboratory mouse, a widely used animal model for comparative studies of the genetic and genomic basis for human health and disease. MGD is the authoritative source for biological reference data related to mouse genes, gene functions, phenotypes and mouse models of human disease. MGD is the primary source for official gene, allele, and mouse strain nomenclature based on the guidelines set by the International Committee on Standardized Nomenclature for Mice. MGD’s biocuration scientists curate information from the biomedical literature and from large and small datasets contributed directly by investigators. In this report we describe significant enhancements to the content and interfaces at MGD, including (i) improvements in the Multi Genome Viewer for exploring the genomes of multiple mouse strains, (ii) inclusion of many more mouse strains and new mouse strain pages with extended query options and (iii) integration of extensive data about mouse strain variants. We also describe improvements to the efficiency of literature curation processes and the implementation of an information portal focused on mouse models and genes for the study of COVID-19.

Background Multi-drug intravenous (IV) therapy is one of the most common medical procedures used in intensive care units (ICUs), operating rooms, oncology wards and many other hospital departments worldwide. As drugs or their solvents are frequently chemically incompatible, many solutions must be administered through separate lumens. When the number of available lumens is too low to facilitate the safe administration of these solutions, additional (peripheral) IV catheters are often required, causing physical discomfort and increasing the risk for catheter related complications. Our objective was to develop and evaluate an algorithm designed to reduce the number of intravenous lumens required in multi-infusion settings by multiplexing the administration of various parenteral drugs and solutions. Methods A multiplex algorithm was developed that schedules the alternating IV administration of multiple incompatible IV solutions through a single lumen, taking compatibility-related, pharmacokinetic and pharmacodynamic constraints of the relevant drugs into account. The conventional scheduling procedure executed by ICU nurses was used for comparison. The number of lumens required by the conventional procedure (LCONV) and multiplex algorithm (LMX) were compared. Results We used data from 175,993 ICU drug combinations, with 2251 unique combinations received by 2715 consecutive ICU patients. The mean ± SD number of simultaneous IV solutions was 2.8 ± 1.6. In 27% of all drug combinations, and 61% of the unique combinations the multiplex algorithm required fewer lumens (p CONV, the reduction in number of lumens by the multiplex algorithm further increased (p 3 lm, versus 12% using the conventional procedure. Conclusion The multiplex algorithm addresses a major issue that occurs in ICUs, operating rooms, oncology wards, and many other hospital departments where several incompatible drugs are infused through a restricted number of lumens. The multiplex algorithm allows for more efficient use of IV lumens compared to the conventional multi-infusion strategy.

Purpose To assess the feasibility of completely excising small breast cancers using the automated, image-guided, single-pass radiofrequency-based breast lesion excision system (BLES) under ultrasound (US) guidance. Methods From February 2018 to July 2019, 22 patients diagnosed with invasive carcinomas ≤ 15 mm at US and mammography were enrolled in this prospective, multi-center, ethics board-approved study. Patients underwent breast MRI to verify lesion size. BLES-based excision and surgery were performed during the same procedure. Histopathology findings from the BLES procedure and surgery were compared, and total excision findings were assessed. Results Of the 22 patients, ten were excluded due to the lesion being > 15 mm and/or being multifocal at MRI, and one due to scheduling issues. The remaining 11 patients underwent BLES excision. Mean diameter of excised lesions at MRI was 11.8 mm (range 8.0–13.9 mm). BLES revealed ten (90.9%) invasive carcinomas of no special type, and one (9.1%) invasive lobular carcinoma. Histopathological results were identical for the needle biopsy, BLES, and surgical specimens for all lesions. None of the BLES excisions were adequate. Margins were usually compromised on both sides of the specimen, indicating that the excised volume was too small. Margin assessment was good for all BLES specimens. One technical complication occurred (retrieval of an empty BLES basket, specimen retrieved during subsequent surgery). Conclusions BLES allows accurate diagnosis of small invasive breast carcinomas. However, BLES cannot be considered as a therapeutic device for small invasive breast carcinomas due to not achieving adequate excision.

BackgroundIn critical care patients, reaching optimal β-lactam concentrations poses challenges, as infections are caused more often by microorganisms associated with higher MICs, and critically ill patients typically have an unpredictable pharmacokinetic/pharmacodynamic profile. Conventional intermittent dosing frequently yields inadequate drug concentrations, while continuous dosing might result in better target attainment. Few studies address cefotaxime concentrations in this population.ObjectivesTo assess total and unbound serum levels of cefotaxime and an active metabolite, desacetylcefotaxime, in critically ill patients treated with either continuously or intermittently dosed cefotaxime.MethodsAdult critical care patients with indication for treatment with cefotaxime were randomized to treatment with either intermittent dosing (1 g every 6 h) or continuous dosing (4 g/24 h, after a loading dose of 1 g). We defined a preset target of reaching and maintaining a total cefotaxime concentration of 4 mg/L from 1 h after start of treatment. CCMO trial registration number NL50809.042.14, Clinicaltrials.gov NCT02560207.ResultsTwenty-nine and 30 patients, respectively, were included in the continuous dosing group and the intermittent dosing group. A total of 642 samples were available for analysis. In the continuous dosing arm, 89.3% met our preset target, compared with 50% in the intermittent dosing arm. Patients not reaching this target had a significantly higher creatinine clearance on the day of admission.ConclusionsThese results support the application of a continuous dosing strategy of β-lactams in critical care patients and the practice of therapeutic drug monitoring in a subset of patients with higher renal clearance and need for prolonged treatment for further optimization, where using total cefotaxime concentrations should suffice.

Objective The Genomic Medicine Working Group of the National Advisory Council for Human Genome Research virtually hosted its 13th genomic medicine meeting titled “Developing a Clinical Genomic Informatics Research Agenda”. The meeting’s goal was to articulate a research strategy to develop Genomics-based Clinical Informatics Tools and Resources (GCIT) to improve the detection, treatment, and reporting of genetic disorders in clinical settings. Materials and Methods Experts from government agencies, the private sector, and academia in genomic medicine and clinical informatics were invited to address the meeting's goals. Invitees were also asked to complete a survey to assess important considerations needed to develop a genomic-based clinical informatics research strategy. Results Outcomes from the meeting included identifying short-term research needs, such as designing and implementing standards-based interfaces between laboratory information systems and electronic health records, as well as long-term projects, such as identifying and addressing barriers related to the establishment and implementation of genomic data exchange systems that, in turn, the research community could help address. Discussion Discussions centered on identifying gaps and barriers that impede the use of GCIT in genomic medicine. Emergent themes from the meeting included developing an implementation science framework, defining a value proposition for all stakeholders, fostering engagement with patients and partners to develop applications under patient control, promoting the use of relevant clinical workflows in research, and lowering related barriers to regulatory processes. Another key theme was recognizing pervasive biases in data and information systems, algorithms, access, value, and knowledge repositories and identifying ways to resolve them.

Funder: Bayer AG, Funder: Università degli Studi di Milano, OBJECTIVES: Preoperative breast magnetic resonance imaging (MRI) can inform surgical planning but might cause overtreatment by increasing the mastectomy rate. The Multicenter International Prospective Analysis (MIPA) study investigated this controversial issue. METHODS: This observational study enrolled women aged 18-80 years with biopsy-proven breast cancer, who underwent MRI in addition to conventional imaging (mammography and/or breast ultrasonography) or conventional imaging alone before surgery as routine practice at 27 centers. Exclusion criteria included planned neoadjuvant therapy, pregnancy, personal history of any cancer, and distant metastases. RESULTS: Of 5896 analyzed patients, 2763 (46.9%) had conventional imaging only (noMRI group), and 3133 (53.1%) underwent MRI that was performed for diagnosis, screening, or unknown purposes in 692/3133 women (22.1%), with preoperative intent in 2441/3133 women (77.9%, MRI group). Patients in the MRI group were younger, had denser breasts, more cancers ≥ 20 mm, and a higher rate of invasive lobular histology than patients who underwent conventional imaging alone (p < 0.001 for all comparisons). Mastectomy was planned based on conventional imaging in 22.4% (MRI group) versus 14.4% (noMRI group) (p < 0.001). The additional planned mastectomy rate in the MRI group was 11.3%. The overall performed first- plus second-line mastectomy rate was 36.3% (MRI group) versus 18.0% (noMRI group) (p < 0.001). In women receiving conserving surgery, MRI group had a significantly lower reoperation rate (8.5% versus 11.7%, p < 0.001). CONCLUSIONS: Clinicians requested breast MRI for women with a higher a priori probability of receiving mastectomy. MRI was associated with 11.3% more mastectomies, and with 3.2% fewer reoperations in the breast conservation subgroup. KEY POINTS: • In 19% of patients of the MIPA study, breast MRI was performed for screening or diagnostic purposes. • The current patient selection to preoperative breast MRI implies an 11% increase in mastectomies, counterbalanced by a 3% reduction of the reoperation rate. • Data from the MIPA study can support discussion in tumor boards when preoperative MRI is under consideration and should be shared with patients to achieve informed decision-making.

Purpose: Self-regulation refers to self-management and self-control, with or without disability. Outcomes of rehabilitation with respect to self-regulation are unclear. This study aims to identify elements of self-regulation that former patients consider important in the context of medical rehabilitation. Materials and methods: Qualitative exploration based on focus group discussions (FGDs). Transcripts were analysed using thematic analysis as well as open coding. Forty individuals participated in seven diagnosis-related FGDs. Results: Six subthemes were raised in the FGDs which could be merged into three main themes. Two main themes are conditional for regaining self-regulation: 1) having insight into one’s condition and abilities (i.e., insight into impairments. consequences of impairments. abilities); 2) to know how to cope with the consequences of the condition (be able to communicate limitations; have to trust in body and functioning). The subject of the last theme 3) is how to apply self-regulation in one’s own life (to make use of abilities and optimize functioning). Conclusions: Three main themes of self-regulation in the context of medical rehabilitation were identified by former patients, partly relating to the ability to self-regulate and partly to the execution of self-regulation. This knowledge can be used to define specific rehabilitation goals and further develop rehabilitation outcome measurement.IMPLICATIONS FOR REHABILITATION Awareness of the fundamental subthemes of self-regulation in rehabilitation will positively contribute to theory building and improve clinical practice (e.g., goal setting). Paying explicit attention to the six subthemes as standard elements of rehabilitation will help to provide a comprehensive view concerning self-regulation. The conceptual model of self-regulation, based on patient perspectives, can contribute to the measurement of rehabilitation outcomes.

The Alliance of Genome Resources (the Alliance) is a combined effort of 7 knowledgebase projects: Saccharomyces Genome Database, WormBase, FlyBase, Mouse Genome Database, the Zebrafish Information Network, Rat Genome Database, and the Gene Ontology Resource. The Alliance seeks to provide several benefits: better service to the various communities served by these projects; a harmonized view of data for all biomedical researchers, bioinformaticians, clinicians, and students; and a more sustainable infrastructure. The Alliance has harmonized cross-organism data to provide useful comparative views of gene function, gene expression, and human disease relevance. The basis of the comparative views is shared calls of orthology relationships and the use of common ontologies. The key types of data are alleles and variants, gene function based on gene ontology annotations, phenotypes, association to human disease, gene expression, protein–protein and genetic interactions, and participation in pathways. The information is presented on uniform gene pages that allow facile summarization of information about each gene in each of the 7 organisms covered (budding yeast, roundworm Caenorhabditis elegans, fruit fly, house mouse, zebrafish, brown rat, and human). The harmonized knowledge is freely available on the alliancegenome.org portal, as downloadable files, and by APIs. We expect other existing and emerging knowledge bases to join in the effort to provide the union of useful data and features that each knowledge base currently provides.

Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism., Nature Communications, 12 (1), ISSN:2041-1723

Background Patient-derived xenografts (PDX) mice models play an important role in preclinical trials and personalized medicine. Sharing data on the models is highly valuable for numerous reasons – ethical, economical, research cross validation etc. The EurOPDX Consortium was established 8 years ago to share such information and avoid duplicating efforts in developing new PDX mice models and unify approaches to support preclinical research. EurOPDX Data Portal is the unified data sharing platform adopted by the Consortium. Main body In this paper we describe the main features of the EurOPDX Data Portal (https://dataportal.europdx.eu/), its architecture and possible utilization by researchers who look for PDX mice models for their research. The Portal offers a catalogue of European models accessible on a cooperative basis. The models are searchable by metadata, and a detailed view provides molecular profiles (gene expression, mutation, copy number alteration) and treatment studies. The Portal displays the data in multiple tools (PDX Finder, cBioPortal, and GenomeCruzer in future), which are populated from a common database displaying strictly mutually consistent views. (Short) Conclusion EurOPDX Data Portal is an entry point to the EurOPDX Research Infrastructure offering PDX mice models for collaborative research, (meta)data describing their features and deep molecular data analysis according to users’ interests.

Visualizing regions of conserved synteny between two genomes is supported by numerous software applications. However, none of the current applications allow researchers to select genome features to display or highlight in blocks of synteny based on the annotated biological properties of the features (e.g., type, function, and/or phenotype association). To address this usability gap, we developed an interactive web-based conserved synteny browser, The Jackson Laboratory (JAX) Synteny Browser. The browser allows researchers to highlight or selectively display genome features in the reference and/or the comparison genome according to the biological attributes of the features. Although the current implementation for the browser is limited to the reference genomes for the laboratory mouse and human, the software platform is intentionally genome agnostic. The JAX Synteny Browser software can be deployed for any two genomes where genome coordinates for syntenic blocks are defined and for which biological attributes of the features in one or both genomes are available in widely used standard bioinformatics file formats. The JAX Synteny Browser is available at: http://syntenybrowser.jax.org/. The code base is available from GitHub: https://github.com/TheJacksonLaboratory/syntenybrowser and is distributed under the Creative Commons Attribution license (CC BY).

Abstract Background Understanding mechanisms underlying specific chemotherapeutic responses in subtypes of cancer may improve identification of treatment strategies most likely to benefit particular patients. For example, triple-negative breast cancer (TNBC) patients have variable response to the chemotherapeutic agent cisplatin. Understanding the basis of treatment response in cancer subtypes will lead to more informed decisions about selection of treatment strategies. Methods In this study we used an integrative functional genomics approach to investigate the molecular mechanisms underlying known cisplatin-response differences among subtypes of TNBC. To identify changes in gene expression that could explain mechanisms of resistance, we examined 102 evolutionarily conserved cisplatin-associated genes, evaluating their differential expression in the cisplatin-sensitive, basal-like 1 (BL1) and basal-like 2 (BL2) subtypes, and the two cisplatin-resistant, luminal androgen receptor (LAR) and mesenchymal (M) subtypes of TNBC. Results We found 20 genes that were differentially expressed in at least one subtype. Fifteen of the 20 genes are associated with cell death and are distributed among all TNBC subtypes. The less cisplatin-responsive LAR and M TNBC subtypes show different regulation of 13 genes compared to the more sensitive BL1 and BL2 subtypes. These 13 genes identify a variety of cisplatin-resistance mechanisms including increased transport and detoxification of cisplatin, and mis-regulation of the epithelial to mesenchymal transition. Conclusions We identified gene signatures in resistant TNBC subtypes indicative of mechanisms of cisplatin. Our results indicate that response to cisplatin in TNBC has a complex foundation based on impact of treatment on distinct cellular pathways. We find that examination of expression data in the context of heterogeneous data such as drug-gene interactions leads to a better understanding of mechanisms at work in cancer therapy response.

Background Distant metastatic disease is frequently observed in inflammatory breast cancer (IBC), with a poor prognosis as a consequence. The aim of this study was to analyze the association of hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) based breast cancer subtypes in stage IV inflammatory breast cancer (IBC) with preferential site of distant metastases and overall survival (OS). Methods For patients with stage IV IBC, diagnosed in the Netherlands between 2005 and 2016, tumors were classified into four breast cancer subtypes: HR+/HER2−, HR+/HER2+, HR−/HER2+, and HR−/HER2−. Patient, tumor, and treatment characteristics and sites of metastases were compared. OS of the subtypes was compared using Kaplan-Meier curves and the log-rank test. Association between subtype and OS was assessed in multivariable models using logistic regression. Results In total, 744 eligible patients were included: 340 (45.7%) tumors were HR+/HER2−, 148 (19.9%) HR−/HER2+, 131 (17.6%) HR+/HER2+, and 125 (16.8%) HR−/HER2−. Bone was the most common metastatic site in all subtypes. A significant predominance of bone metastases was found in HR+/HER2− IBC (71.5%), and liver and lung metastases in the HR−/HER2+ (41.2%) and HR−/HER2− (40.8%) subtypes, respectively. In multivariable analysis, the HR−/HER2− subtype was associated with significantly worse OS as compared to the other subtypes. Conclusion Breast cancer subtypes in stage IV IBC are associated with distinct patterns of metastatic spread and display notable differences in OS. The use of breast cancer subtypes can guide a more patient-tailored staging directed to metastatic site and extend of disease.

Male breast cancer (MBC) is extremely rare and accounts for less than 1% of all breast malignancies. Therefore, clinical management of MBC is currently guided by research on the disease in females. In this study, DNA obtained from 45 formalin-fixed paraffin-embedded (FFPE) MBCs with and 90 MBCs (52 FFPE and 38 fresh-frozen) without matched normal tissues was subjected to massively parallel sequencing targeting all exons of 1943 cancer-related genes. The landscape of mutations and copy number alterations was compared to that of publicly available estrogen receptor (ER)-positive female breast cancers (smFBCs) and correlated to prognosis. From the 135 MBCs, 90% showed ductal histology, 96% were ER-positive, 66% were progesterone receptor (PR)-positive, and 2% HER2-positive, resulting in 50, 46 and 4% luminal A-like, luminal B-like and basal-like cases, respectively. Five patients had Klinefelter syndrome (4%) and 11% of patients harbored pathogenic BRCA2 germline mutations. The genomic landscape of MBC to some extent recapitulated that of smFBC, with recurrent PIK3CA (36%) and GATA3 (15%) somatic mutations, and with 40% of the most frequently amplified genes overlapping between both sexes. TP53 (3%) somatic mutations were significantly less frequent in MBC compared to smFBC, whereas somatic mutations in genes regulating chromatin function and homologous recombination deficiency-related signatures were more prevalent. MDM2 amplifications were frequent (13%), correlated with protein overexpression (P = 0.001) and predicted poor outcome (P = 0.007). In conclusion, despite similarities in the genomic landscape between MBC and smFBC, MBC is a molecularly unique and heterogeneous disease requiring its own clinical trials and treatment guidelines.

The Alliance of Genome Resources (Alliance) is a consortium of the major model organism databases and the Gene Ontology that is guided by the vision of facilitating exploration of related genes in human and well-studied model organisms by providing a highly integrated and comprehensive platform that enables researchers to leverage the extensive body of genetic and genomic studies in these organisms. Initiated in 2016, the Alliance is building a central portal (www.alliancegenome.org) for access to data for the primary model organisms along with gene ontology data and human data. All data types represented in the Alliance portal (e.g. genomic data and phenotype descriptions) have common data models and workflows for curation. All data are open and freely available via a variety of mechanisms. Long-term plans for the Alliance project include a focus on coverage of additional model organisms including those without dedicated curation communities, and the inclusion of new data types with a particular focus on providing data and tools for the non-model-organism researcher that support enhanced discovery about human health and disease. Here we review current progress and present immediate plans for this new bioinformatics resource.

Objectives Vacuum-assisted biopsy (VAB) of the breast seems unsuitable for rapid processing due to large size. We tested microwave-based acceleration. Methods As a proof-of-principle study, 9-gauge VAB specimens were taken from eight mastectomy specimens. Forty-two biopsy specimens were processed. Quality of H&E was evaluated in 84 slides, and estrogen receptor (ER), progesterone receptor (PR), E-cadherin, and human epidermal growth factor receptor 2 (HER2) stains were evaluated in six slides. Preoperative biopsy specimens were used as a control. Results Diagnostic quality of H&E slides was good in 87%, reasonable in 12%, and low in 1%. Quality of E-cadherin was good in 75% and reasonable in 25%. Quality of ER was good in 83% and reasonable in 17%. PR and both HER2 immunohistochemistry and fluorescence in situ hybridization were good in all slides. Quality of experimental slides was similar to control slides. Conclusions Nine-gauge VAB specimens can be processed within 4 hours. Slides are suitable for all routine pathologic stains. This enables a same-day diagnosis.

Dramatic advances in technologies for assessing genomic variation and understanding the influence of genomic variants on health and disease are propelling the transition of genomics from the research laboratory into clinical care. “Genomic medicine,” or the use of genomic information about an individual as part of their clinical care, is increasingly gaining acceptance in routine practice, including using genomics for assessing disease risk in individuals and their families, diagnosing rare and undiagnosed diseases, and improving drug safety and efficacy. Here we describe the major concepts and measures of genomic variation currently of clinical importance, discuss approaches to interpreting genomic sequence variants, identify publicly available tools and resources for genomic test interpretation, and address several key barriers in using genomic information in routine clinical practice.

Breast cancer treatment depends on human epidermal growth factor receptor-2 (HER2) status, which is often determined using dual probe fluorescence in situ hybridisation (FISH). Hereby, also loss and gain of the centromere of chromosome 17 (CEP17) can be observed (HER2 is located on chromosome 17). CEP17 gain can lead to difficulty in interpretation of HER2 status, since this might represent true polysomy. With this study we investigated whether isolated polysomy is present and how this effects HER2 status in six breast cancer cell lines and 97 breast cancer cases, using HER2 FISH and immunohistochemistry, DNA ploidy assessment and multiplex ligation dependent probe amplification. We observed no isolated polysomy of chromosome 17 in any cell line. However, FISH analysis did show CEP17 gain in five of six cell lines, which reflected gains of the whole chromosome in metaphase spreads and aneuploidy with gain of multiple chromosomes in all these cases. In patients’ samples, gain of CEP17 indeed correlated with aneuploidy of the tumour (91.1%; p

Drug-tolerance is an acute defense response prior to a fully drug-resistant state and tumor relapse, however there are few therapeutic agents targeting drug-tolerance in the clinic. Here we show that miR-147b initiates a reversible tolerant-state to the EGFR inhibitor osimertinib in non-small cell lung cancer. With miRNA-seq analysis we find that miR-147b is the most upregulated microRNA in osimertinib-tolerant and EGFR mutated lung cancer cells. Whole transcriptome analysis of single-cell derived clones reveals a link between osimertinib-tolerance and pseudohypoxia responses irrespective of oxygen levels. Further metabolomics and genetic studies demonstrate that osimertinib-tolerance is driven by miR-147b repression of VHL and succinate dehydrogenase linked to the tricarboxylic acid cycle and pseudohypoxia pathways. Finally, pretreatment with a miR-147b inhibitor delays osimertinib-associated drug tolerance in patient-derived three-dimensional (3D) structures. This link between miR-147b and tricarboxylic acid cycle may provide promising targets for preventing tumor relapse.

Objectives The purpose of this study is to evaluate the predictive value of the amount of fibroglandular tissue (FGT) and background parenchymal enhancement (BPE), measured at baseline on breast MRI, for breast cancer development and risk of false-positive findings in women at increased risk for breast cancer. Methods Negative baseline MRI scans of 1533 women participating in a screening program for women at increased risk for breast cancer between January 1, 2003, and January 1, 2014, were selected. Automated tools based on deep learning were used to obtain quantitative measures of FGT and BPE. Logistic regression using forward selection was used to assess relationships between FGT, BPE, cancer detection, false-positive recall, and false-positive biopsy. Results Sixty cancers were detected in follow-up. FGT was only associated to short-term cancer risk; BPE was not associated with cancer risk. High FGT and BPE did lead to more false-positive recalls at baseline (OR 1.259, p = 0.050, and OR 1.475, p = 0.003) and to more frequent false-positive biopsies at baseline (OR 1.315, p = 0.049, and OR 1.807, p = 0.002), but were not predictive for false-positive findings in subsequent screening rounds. Conclusions FGT and BPE, measured on baseline MRI, are not predictive for overall breast cancer development in women at increased risk. High FGT and BPE lead to more false-positive findings at baseline. Key Points • Amount of fibroglandular tissue is only predictive for short-term breast cancer risk in women at increased risk. • Background parenchymal enhancement measured on baseline MRI is not predictive for breast cancer development in women at increased risk. • High amount of fibroglandular tissue and background parenchymal enhancement lead to more false-positive findings at baseline MRI. Electronic supplementary material The online version of this article (10.1007/s00330-019-06020-2) contains supplementary material, which is available to authorized users.

Objectives: As a result of the increasing number of diagnostic scans, incidental findings (IFs) are more frequently encountered during oncological work-up in patients with head and neck squamous cell carcinomas (HNSCC). IFs are unintentional discoveries found on diagnostic imaging. Relevant IFs implicate clinical consequences, resulting in delay in oncologic treatment initiation, which is associated with unfavorable outcomes. This study is the first to investigate the incidence and nature of IFs over the years and establish the effect of relevant IFs on delay.Material and methods: This retrospective study compared two time periods (2010 & ndash;2011 and 2016 & ndash;2017), described associations between relevant IFs and delay in carepathway interval (days between first visit and treatment initiation) and assessed the effect of relevant IFs on overall two-year survival. Results: In total, 592 patients were included. At least one IF was found in 61.5% of the patients, most frequently on chest-CT. In 128 patients (21.6%) a relevant IF was identified, resulting for the majority in radiologist recommendations (e.g. additional scanning). Presence of a relevant IF was an independent significant factor associated with delay in treatment initiation. The risk of dying was higher for patients with a relevant IF, although not significant in the multivariable model (HR: 1.46, p = 0.079).Conclusion: In diagnostic work-up for HNSCC patients, relevant IFs are frequently encountered. As the frequency of additional imaging rises over the years, the number of IFs increased simultaneously. These relevant IFs yield clinical implications and this study described that relevant IFs result in significant delay in treatment initiation.

Purpose: Potential drug-drug interactions (pDDIs) may harm patients admitted to the Intensive Care Unit (ICU). Due to the patient's critical condition and continuous monitoring on the ICU, not all pDDIs are clinically relevant. Clinical decision support systems (CDSSs) warning for irrelevant pDDIs could result in alert fatigue and overlooking important signals. Therefore, our aim was to describe the frequency of clinically relevant pDDIs (crpDDIs) to enable tailoring of CDSSs to the ICU setting. Materials & methods: In this multicenter retrospective observational study, we used medication administration data to identify pDDIs in ICU admissions from 13 ICUs. Clinical relevance was based on a Delphi study in which intensivists and hospital pharmacists assessed the clinical relevance of pDDIs for the ICU setting. Results: The mean number of pDDIs per 1000 medication administrations was 70.1, dropping to 31.0 when con -sidering only crpDDIs. Of 103,871 ICU patients, 38% was exposed to a crpDDI. The most frequently occurring crpDDIs involve QT-prolonging agents, digoxin, or NSAIDs. Conclusions: Considering clinical relevance of pDDIs in the ICU setting is important, as only half of the detected pDDIs were crpDDIs. Therefore, tailoring CDSSs to the ICU may reduce alert fatigue and improve medication safety in ICU patients. ? 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Parents of children with ADHD experience several difficulties while raising their children and report lower levels of knowledge about their children’s life and behaviors. A recent study found that low levels of parental knowledge mediated the association between ADHD symptoms and risk-taking behavior (RTB) in adolescents. The current study aimed to investigate this previous finding further by replicating it, by taking peer influence into account as additional social factor of importance and by extending it and also investigate the role of parental knowledge in the association between ADHD symptoms and homework problems. Three studies were performed: study 1 (N=234) replicated previous work on parental knowledge mediating the association between ADHD symptoms and RTB, study 2 (pre-registered, N=313) added peer influence, and study 3 (pre-registered, N=315) assessed whether parental knowledge mediated the association between ADHD symptoms and homework behavior. Parental knowledge consistently mediated the association between ADHD symptoms on one hand and RTB and homework problems on the other, and also predicted stronger resistance to peer influence. Because parental knowledge was repeatedly linked to ADHD-related problems, it seems promising to include parental knowledge in treatment of ADHD-related problems in adolescents, by improving the parent-child relationship. Future studies should test more directly how improvement of the parent-child relationship can be used to optimize parental knowledge, which in its turn reduces ADHD-related problems. Electronic supplementary material The online version of this article (10.1007/s00787-020-01579-4) contains supplementary material, which is available to authorized users.

Background This study aimed to examine the association between preoperative magnetic resonance imaging (MRI) and surgical margin involvement, as well as to determine the factors associated with positive resection margins in screen-detected breast cancer patients undergoing breast-conserving surgery (BCS). Methods Breast cancer patients eligible for BCS and diagnosed after biennial screening mammography in the south of The Netherlands (2008–2017) were retrospectively included. Missing values were imputed and multivariable regression analyses were performed to analyze whether preoperative MRI was related to margin involvement after BCS, as well as to examine what factors were associated with positive resection margins, defined as more than focally (>4 mm) involved. Results Overall, 2483 patients with invasive breast cancer were enrolled, of whom 123 (5.0%) had more than focally involved resection margins. In multivariable regression analyses, preoperative MRI was associated with a reduced risk of positive resection margins after BCS (adjusted odds ratio [OR] 0.56, 95% confidence interval [CI] 0.33–0.96). Lobular histology (adjusted OR 2.86, 95% CI 1.68–4.87), large tumor size (per millimeter increase, adjusted OR 1.05, 95% CI 1.03–1.07), high (>75%) mammographic density (adjusted OR 3.61, 95% CI 1.07–12.12), and the presence of microcalcifications (adjusted OR 4.45, 95% CI 2.69–7.37) and architectural distortions (adjusted OR 1.85, 95% CI 1.01–3.40) were independently associated with positive resection margins after BCS. Conclusions Preoperative MRI was associated with lower risk of positive resection margins in patients with invasive breast cancer eligible for BCS using multivariable analysis. Furthermore, specific mammographic characteristics and tumor characteristics were independently associated with positive resection margins after BCS.

Importance Silicone breast implants have been on the market for breast augmentation or breast reconstruction for approximately 60 years but may lead to medical complications, also called breast implant illness. Objective To evaluate the existence of silicone gel bleed and migration over a long time period, including the period in which the newer cohesive silicone gel breast implants were used. Design, setting, and participants In this single-center case series, capsule tissue and lymph node samples were collected from women who underwent removal or revision of silicone breast implants from January 1, 1986, to August 18, 2020, and data were extracted from the pathological reports and revision of the histology if data were missing. All tissues were examined using standard light microscopy, some extended with modified oil red O staining and energy-dispersive radiographic spectroscopy. A total of 365 women had capsular tissue removed, including 15 patients who also had lymph nodes removed, and 24 women had only lymph nodes removed. Data were analyzed from January to May 2021. Exposures Silicone breast implants. Main outcomes and measures The main outcome was presence or absence of silicones inside or outside the capsule. One-way analysis of variance was used to determine significance between groups. Results Among a total of 389 women with silicone breast implants (mean [SD] age, 50.5 [11.2] years), 384 women (98.8%) had silicone particles present in the tissues, indicating silicone gel bleed. In 337 women (86.6%), silicone particles were observed outside the capsule (ie, in tissues surrounding the capsule and/or lymph nodes), indicating silicone migration. In 47 women (12.1%), silicone particles were only present within the capsule. In 5 women (1.2%), no silicone particles were detected in the tissues. Patients were divided into 2 groups, with 46 women who received cohesive silicone gel breast implants and 343 women who received either an older or a newer type of breast implant. There were no differences in silicone gel bleed or migration between groups (silicone detected outside or inside capsule: 44 women [95.7%] vs 340 women [99.1%]; P = .19). Conclusions and relevance In this case series including women with noncohesive or cohesive silicone gel breast implants, silicone leakage occurred in 98.8% of women, indicating silicone gel bleed, and in 86.6% of women, migration of silicone particles outside the capsule was detected.

The tumour microenvironment has been shown to be a valuable source of prognostic information for different cancer types. This holds in particular for triple negative breast cancer (TNBC), a breast cancer subtype for which currently no prognostic biomarkers are established. Although different methods to assess tumour infiltrating lymphocytes (TILs) have been published, it remains unclear which method (marker, region) yields the most optimal prognostic information. In addition, to date, no objective TILs assessment methods are available. For this proof of concept study, a subset of our previously described TNBC cohort (n = 94) was stained for CD3, CD8 and FOXP3 using multiplex immunohistochemistry and subsequently imaged by a multispectral imaging system. Advanced whole-slide image analysis algorithms, including convolutional neural networks (CNN) were used to register unmixed multispectral images and corresponding H&E sections, to segment the different tissue compartments (tumour, stroma) and to detect all individual positive lymphocytes. Densities of positive lymphocytes were analysed in different regions within the tumour and its neighbouring environment and correlated to relapse free survival (RFS) and overall survival (OS). We found that for all TILs markers the presence of a high density of positive cells correlated with an improved survival. None of the TILs markers was superior to the others. The results of TILs assessment in the various regions did not show marked differences between each other. The negative correlation between TILs and survival in our cohort are in line with previous studies. Our results provide directions for optimizing TILs assessment methodology., Highlights • Deep learning algorithms enable objective assessment of biomarkers. • Automated assessment of tumour infiltrating lymphocytes is feasible. • Tumour infiltrating lymphocytes are prognostic in triple negative breast cancer.

Specific mutations in the RET proto-oncogene are associated with multiple endocrine neoplasia type 2A, a hereditary syndrome characterized by tumorigenesis in multiple glandular elements. In rare instances, MEN2A-associated germline RET mutations have also occurred with non-MEN2A associated cancers. One such germline mutant RET mutation occurred concomitantly in a young adult diagnosed with alveolar rhabdomyosarcoma, a pediatric and young adult soft-tissue cancer with a generally poor prognosis. Although tumor tissue samples were initially unable to provide a viable cell culture for study, tumor tissues were sequenced for molecular characteristics. Through a hierarchical clustering approach, the index case sample was matched to several genetically similar cell models, which were transformed to express the same mutant RET as the index case and used to explore potential therapeutic options for mutant RET-bearing alveolar rhabdomyosarcoma. We also determined whether the RET mutation associated with the index case caused synthetic lethality to select clinical agents. From our investigation, we did not identify synthetic lethality associated with the expression of that patient's RET variant, and overall we did not find experimental evidence for the role of RET in rhabdomyosarcoma progression.

Summary Preoperative histopathological classification determines the primary surgical approach in endometrial carcinoma (EC) patients but has only moderate agreement between preoperative and postoperative diagnosis. The aim of the PIpelle Prospective ENDOmetrial carcinoma (PIPENDO) study is to determine whether histopathological assessment and a small panel of diagnostic biomarkers decreases discrepancies between preoperative and postoperative diagnosis in EC. Preoperative endometrial tissue of 378 included patients with EC was stained with 15 different antibodies. Clinically relevant discrepancies in grade or histological subtype between original preoperative and reviewed postoperative diagnosis were observed in 75 (20%) patients. Highest clinically relevant discrepancy was found in grade 2 ECs (20%), compared to 5% and 14% in respectively grade 1 and 3 endometrioid endometrial carcinomas (EECs). A practical two-biomarker panel with PR and p53 improved diagnostic accuracy (AUC = 0.92; 95%CI = 0.88–0.95) compared to solely morphological evaluation (AUC = 0.86). In preoperative high-grade EC, the diagnostic accuracy of histological subtype was improved by a three–immunohistochemical biomarker panel (PR, IMP3, and L1CAM) (AUC = 0.93; 95%CI = 0.88–0.98) compared to solely morphological evaluation (AUC = 0.81). In conclusion to improve correct preoperative diagnosis in EC, we recommend use of a panel of at least two easily accessible immunohistochemical biomarkers (PR and p53), only in grade 2 ECs. Overall, this will reduce clinically relevant discrepancies in tumor grade and subtype with postoperative diagnosis with 6% (from 20% to 14%). Addition of PR, IMP3, and L1CAM for histological subtyping in high-grade EECs resulted in a further decrease in discrepancies with 8% (from 20% to 12%).

Objectives Preoperative breast magnetic resonance imaging (MRI) can inform surgical planning but might cause overtreatment by increasing the mastectomy rate. The Multicenter International Prospective Analysis (MIPA) study investigated this controversial issue. Methods This observational study enrolled women aged 18–80 years with biopsy-proven breast cancer, who underwent MRI in addition to conventional imaging (mammography and/or breast ultrasonography) or conventional imaging alone before surgery as routine practice at 27 centers. Exclusion criteria included planned neoadjuvant therapy, pregnancy, personal history of any cancer, and distant metastases. Results Of 5896 analyzed patients, 2763 (46.9%) had conventional imaging only (noMRI group), and 3133 (53.1%) underwent MRI that was performed for diagnosis, screening, or unknown purposes in 692/3133 women (22.1%), with preoperative intent in 2441/3133 women (77.9%, MRI group). Patients in the MRI group were younger, had denser breasts, more cancers ≥ 20 mm, and a higher rate of invasive lobular histology than patients who underwent conventional imaging alone (p p p p Conclusions Clinicians requested breast MRI for women with a higher a priori probability of receiving mastectomy. MRI was associated with 11.3% more mastectomies, and with 3.2% fewer reoperations in the breast conservation subgroup. Key Points • In 19% of patients of the MIPA study, breast MRI was performed for screening or diagnostic purposes. • The current patient selection to preoperative breast MRI implies an 11% increase in mastectomies, counterbalanced by a 3% reduction of the reoperation rate. • Data from the MIPA study can support discussion in tumor boards when preoperative MRI is under consideration and should be shared with patients to achieve informed decision-making.

Contains fulltext : 232535.pdf (Publisher’s version ) (Closed access) There is no consensus on the cutoff for positivity of estrogen receptor (ER) and progesterone receptor (PR) in endometrial cancer (EC). Therefore, we determined the cutoff value for ER and PR expression with the strongest prognostic impact on the outcome. Immunohistochemical expression of ER and PR was scored as a percentage of positive EC cell nuclei. Cutoff values were related to disease-specific survival (DSS) and disease-free survival (DFS) using sensitivity, specificity, and multivariable regression analysis. The results were validated in an independent cohort. The study cohort (n = 527) included 82% of grade 1-2 and 18% of grade 3 EC. Specificity for DSS and DFS was highest for the cutoff values of 1-30%. Sensitivity was highest for the cutoff values of 80-90%. ER and PR expression were independent markers for DSS at cutoff values of 10% and 80%. Consequently, three subgroups with distinct clinical outcomes were identified: 0-10% of ER/PR expression with, unfavorable outcome (5-year DSS = 75.9-83.3%); 20-80% of ER/PR expression with, intermediate outcome (5-year DSS = 93.0-93.9%); and 90-100% of ER/PR expression with, favorable outcome (5-year DSS = 97.8-100%). The association between ER/PR subgroups and outcomes was confirmed in the validation cohort (n = 265). We propose classification of ER and PR expression based on a high-risk (0-10%), intermediate-risk (20-80%), and low-risk (90-100%) group.

Contains fulltext : 225795.pdf (Publisher’s version ) (Closed access) Despite its high diagnostic performance, the use of breast MRI in the preoperative setting is controversial. It has the potential for personalized surgical management in breast cancer patients, but two of three randomized controlled trials did not show results in favor of its introduction for assessing the disease extent before surgery. Meta-analyses showed a higher mastectomy rate in women undergoing preoperative MRI compared to those who do not. Nevertheless, preoperative breast MRI is increasingly used and a survey from the American Society of Breast Surgeons showed that 41% of respondents ask for it in daily practice. In this context, a large-scale observational multicenter international prospective analysis (MIPA study) was proposed under the guidance of the European Network for the Assessment of Imaging in Medicine (EuroAIM). The aims were (1) to prospectively and systematically collect data on consecutive women with a newly diagnosed breast cancer, not candidates for neoadjuvant therapy, who are offered or not offered breast MRI before surgery according to local practice; (2) to compare these two groups in terms of surgical and clinical endpoints, adjusting for covariates. The underlying hypotheses are that MRI does not cause additional mastectomies compared to conventional imaging, while reducing the reoperation rate in all or in subgroups of patients. Ninety-six centers applied to a web-based call; 36 were initially selected based on volume and quality standards; 27 were active for enrollment. On November 2018, the target of 7000 enrolled patients was reached. The MIPA study is presently at the analytic phase. Key Points • Breast MRI has a high diagnostic performance but its utility in the preoperative setting is controversial. • A large-scale observational multicenter prospective study was launched to compare women receiving with those not receiving preoperative MRI. • Twenty-seven centers enrolled more than 7000 patients. The study is presently at the analytic phase.

Poor joint health is a significant burden to society. Millions of people suffer from some form of joint-related disorder or disease, most often osteoarthritis (OA). It was hypothesized that chicken eggshell membrane (EM) is effective in the regeneration of cartilage and/or immunomodulation (oral tolerance), and as such relieves pain and stiffness in joints commonly affected in arthritis. We tested this hypothesis in a double-blind, placebo-controlled EM intervention study. Of 150 male and female volunteers, 40–75 years of age and diagnosed with knee OA, 75 were randomly assigned to the EM intervention group and 75 to the placebo group. During 12 weeks, subjects received a daily capsule containing either 300 mg of EM or a placebo. The main primary dependent variable consisted of self-reported pain ratings on a Numerical Rating Scale Pain (NRS-P) 6 weeks after study start. As secondary dependent variables served NRS-P scores collected after 12 weeks, and Knee injury and self-reported Osteoarthritis Outcome Scores (Knee injury and Osteoarthritis Outcome Scores [KOOS]). NRS-P scores decreased for both groups at approximately the same rate, but only EM relieved self-reported pain scores obtained with the KOOS questionnaire starting 1 week after initiation of treatment. This effect was significant for two of five KOOS category scores, that is, “Pain” and “Daily Life” functioning, aggregate pain, and functioning scores composed of complaint ratings for a wide variety of daily activities. These scores showed long-lasting improvement, and demonstrated that EM extract successfully reliefs knee OA pain and contributes to daily life functioning.

Inflammation is a key physiological phenomenon that can be pervasive when dysregulated. Persistent chronic inflammation precedes several pathophysiological conditions forming one of the critical cellular homeostatic checkpoints. With a steady global surge in inflammatory diseases, it is imperative to delineate underlying mechanisms and design suitable drug molecules targeting the cellular partners that mediate and regulate inflammation. Nicotinic acetylcholine receptors have a confirmed role in influencing inflammatory pathways and have been a subject of scientific scrutiny underlying drug development in recent years. Drugs designed to target allosteric sites on the nicotinic acetylcholine receptors present a unique opportunity to unravel the role of the cholinergic system in regulating and restoring inflammatory homeostasis. Such a therapeutic approach holds promise in treating several inflammatory conditions and diseases with inflammation as an underlying pathology. Here, we briefly describe the potential of cholinergic allosterism and some allosteric modulators as a promising therapeutic option for the treatment of neuroinflammation.

Mice xenotransplanted with human cells and/or expressing human gene products (also known as “humanized mice”) recapitulate the human evolutionary specialization and diversity of genotypic and phenotypic traits. These models can provide a relevant in vivo context for understanding of human‐specific physiology and pathologies. Humanized mice have advanced toward mainstream preclinical models and are now at the forefront of biomedical research. Here, we considered innovations and challenges regarding the reconstitution of human immunity and human tissues, modeling of human infections and cancer, and the use of humanized mice for testing drugs or regenerative therapy products. As the number of publications exploring different facets of humanized mouse models has steadily increased in past years, it is becoming evident that standardized reporting is needed in the field. Therefore, an international community‐driven resource called “Minimal Information for Standardization of Humanized Mice” (MISHUM) has been created for the purpose of enhancing rigor and reproducibility of studies in the field. Within MISHUM, we propose comprehensive guidelines for reporting critical information generated using humanized mice., Humanized mice are at the forefront of biomedical research and becoming more mainstream preclinical models. This comprehensive review talks about innovations and challenges regarding the reconstitution of human immunity and introduces “Minimal Information for Standardization of Humanized Mice” (MISHUM).